Inhalant abuse presents a serious, under-appreciated public health problem in the United States and worldwide. Basic research on inhalants has lagged far behind that on most other classes of abused drugs. Several factors may be responsible for the paucity of scientific studies in the area. Lack of appropriate methods to explore the abuse-related in vivo neurochemical effects of inhalants is clearly one factor. However, another more fundamental impediment to advancing our basic understanding of inhalants is the sheer size and heterogeneity of the class itself. It is currently unclear to what extent inhalants should even be considered a formal drug class since it is the only class based upon route of administration rather than pharmacological mechanisms of action. It is our hypothesis that inhalant drug discrimination in mice can be used to gain basic information concerning the in vivo abuse-related neurochemical effects of inhalants as well as permit inhalants to be grouped into pharmacologically-based subclasses. In Aim 1 we will train groups of mice to discriminate one of four different inhalants from air: toluene, 1,1,1-trichlroethane (TCE), isoflurane or nitrous oxide. We will subsequently conduct cross-tests among these four compounds as well as with other representative volatile solvents and volatile anesthetics. We hypothesize that these cross-tests will reveal several distinct inhalant groups. If confirmed these findings would support our contention that subclasses of inhalants can be differentiated based on their discriminative stimuli. In Aim 2 we will determine the pharmacological mechanisms of action of toluene, TCE, isoflurane and nitrous oxide. In the case of toluene and TCE we will focus on exploring the GABAA receptor positive modulatory effects of these compounds revealed in our prior studies. Specifically we will perform cross-tests and antagonism experiments with compounds that selectively modulate GABAA receptors composed of particular subunits. In the case of the isoflurane discrimination we will also examine other potential targets based on our preliminary data as well as the available in vivo and in vitro literature. As we lack preliminary data with nitrous oxide our choice of cross-test compounds will initially be based on the literature and then further refined as sufficient drug discrimination results are generated. In Aim 3 will we confirm the pharmacological mechanisms of action underlying our theoretical inhalant subclasses. We will train animals to discriminate three additional inhalant selected based on their similarity to toluene, TCE and isoflurane and conduct cross-tests with compounds identified in Aim 2 as being capable of differentiating between these hypothetical inhalants subclasses. A similar pattern of cross-substitution results with these newly trained inhalants will confirm the pharmacological validity of our inhalant classification framework as well as provide important insights on the neuropharmacology of these compounds. PUBLIC HEALTH RELEVANCE: Advancements in the treatment and prevention of inhalant abuse are hampered by a poor understanding of the neuropharmacology underlying the abuse-related behavioral effects of these compounds. The present study will use drug discrimination in mice to provide insights into the mechanisms of action abused inhalants as well as aid in the development of a rational scientifically-based framework for classifying these compounds.